title: Noncanonical Wnt signaling mediates androgen-dependent tumor growth in a mouse model of prostate cancer.
abstract: Prostate cancer development is associated with hyperactive androgen signaling. However, the molecular link between androgen receptor (AR) function and humoral factors remains elusive. A prostate cancer mouse model was generated by selectively mutating the AR threonine 877 into alanine in prostatic epithelial cells through Cre-ERT2-mediated targeted somatic mutagenesis. Such AR point mutant mice (ARpe-T877A/Y) developed hypertrophic prostates with responses to both an androgen antagonist and estrogen, although no prostatic tumor was seen. In prostate cancer model transgenic mice, the onset of prostatic tumorigenesis as well as tumor growth was significantly potentiated by introduction of the AR T877A mutation into the prostate. Genetic screening of mice identified Wnt-5a as an activator. Enhanced Wnt-5a expression was detected in the malignant prostate tumors of patients, whereas in benign prostatic hyperplasia such aberrant up-regulation was not obvious. These findings suggest that a noncanonical Wnt signal stimulates development of prostatic tumors with AR hyperfunction.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Sayuri
authors.initials: S
authors.lastname: Takahashi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Maiko
authors.initials: M
authors.lastname: Okada
authors.forename: Kazuki
authors.initials: K
authors.lastname: Inoue
authors.forename: Takashi
authors.initials: T
authors.lastname: Ueda
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takada
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Watabe
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Toru
authors.initials: T
authors.lastname: Fukuda
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Chihiro
authors.initials: C
authors.lastname: Akimoto
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Fujimura
authors.forename: Maiko
authors.initials: M
authors.lastname: Hoshino
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Imai
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Minami
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Tadaichi
authors.initials: T
authors.lastname: Kitamura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
mesh_terms: D019943:Amino Acid Substitution; D000728:Androgens / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000728:Androgens; D011944:Receptors, Androgen; D051153:Wnt Proteins